Myocardium conditioning using myocardial and parasympathetic stimulation

ABSTRACT

Various system embodiments comprise a neural stimulator, a pulse generator, and a controller. The neural stimulator is adapted to generate a neural stimulation signal. The pulse generator is adapted to generate a pacing signal to provide myocardium pacing. The controller is adapted to control the neural stimulator and the pulse generator to provide a cardioprotective conditioning therapy. The conditioning therapy includes neural stimulation to elicit a parasympathetic response and myocardium pacing. Other aspects and embodiments are provided herein.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.11/381,211, filed May 2, 2006, which is hereby incorporated by referencein its entirety.

TECHNICAL FIELD

This application relates generally to the treatment of heart diseaseand, more particularly, to systems, devices and methods to providemyocardial conditioning using myocardial and parasympatheticstimulation.

BACKGROUND

The heart is the center of a person's circulatory system. The leftportions of the heart draw oxygenated blood from the lungs and pump itto the organs of the body to provide the organs with their metabolicneeds for oxygen. The right portions of the heart draw deoxygenatedblood from the body organs and pump it to the lungs where the blood getsoxygenated. Contractions of the myocardium provide these pumpingfunctions. In a normal heart, the sinoatrial node, the heart's naturalpacemaker, generates electrical impulses that propagate through anelectrical conduction system to various regions of the heart to excitethe myocardial tissues of these regions. Coordinated delays in thepropagations of the electrical impulses in a normal electricalconduction system causes the various portions of the heart to contractin synchrony, which efficiently pumps the blood. Blocked or abnormalelectrical conduction or deteriorated myocardial tissue causesdysynchronous contraction of the heart, resulting in poor hemodynamicperformance, including a diminished blood supply to the heart and therest of the body. Heart failure occurs when the heart fails to pumpenough blood to meet the body's metabolic needs.

An occlusion of a blood vessel such as a coronary artery interruptsblood supply to the myocardium, which deprives the myocardium isdeprived of adequate oxygen and metabolite removal, and results incardiac ischemia. Myocardial infarction (MI) is the necrosis of portionsof the myocardial tissue which results from cardiac ischemia. Thenecrotic tissue, known as infarcted tissue, loses the contractileproperties of normal, healthy myocardial tissue. The overallcontractility of the myocardium is weakened, resulting in an impairedhemodynamic performance. Following an MI, cardiac remodeling starts withexpansion of the region of infarcted tissue and progresses to a chronic,global expansion in the size and change in the shape of the entire leftventricle. The consequences include a further impaired hemodynamicperformance and a significantly increased risk of developing heartfailure, as well as a risk of suffering recurrent MI.

Therefore, there is a need to protect the myocardium from injuriesassociated with ischemic events, including MI.

SUMMARY

Various aspects of the present subject matter relate to a system.Various system embodiments comprise a neural stimulator, a pulsegenerator, and a controller. The neural stimulator is adapted togenerate a neural stimulation signal. The pulse generator is adapted togenerate a pacing signal to provide myocardium pacing. The controller isadapted to control the neural stimulator and the pulse generator toprovide a cardioprotective conditioning therapy. The conditioningtherapy includes neural stimulation to elicit a parasympathetic responseand myocardium pacing.

Various aspects of the present subject matter relate to a method.According to various embodiments of the method, cardioprotective therapyis provided to treat heart disease. The cardioprotective therapyincludes cardioprotective pacing therapy, and cardioprotective neuralstimulation therapy to elicit a parasympathetic response.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates therapies to affect a PI3-Akt prosurvival kinase,according to various embodiments of the present subject matter.

FIGS. 2A-2B illustrate myocardium preconditioning and myocardiumpostconditioning, respectively, according to various embodiments of thepresent subject matter.

FIGS. 3A-3B illustrate simultaneous and sequential, respectively,delivery of parasympathetic stimulation therapy and pacing therapy,according to various embodiments of the present subject matter.

FIGS. 4A-4C illustrate methods for providing pacing and parasympatheticstimulation therapies to condition myocardium, according to variousembodiments of the present subject matter.

FIG. 5 illustrates a device embodiment for providing pacing andparasympathetic stimulation therapies to condition myocardium, accordingto various embodiments of the present subject matter.

FIG. 6 illustrates a device embodiment for providing pacing andparasympathetic stimulation to condition myocardium as part ofpreconditioning and postconditioning therapies, according to variousembodiments of the present subject matter.

FIG. 7 illustrates an implantable medical device (IMD) having a neuralstimulation (NS) component and cardiac rhythm management (CRM)component, according to various embodiments of the present subjectmatter.

FIG. 8 shows a system diagram of an embodiment of a microprocessor-basedimplantable device, according to various embodiments.

FIG. 9 illustrates a system including an implantable medical device(IMD) and an external system or device, according to various embodimentsof the present subject matter.

FIG. 10 illustrates a system including an external device, animplantable neural stimulator (NS) device and an implantable cardiacrhythm management (CRM) device, according to various embodiments of thepresent subject matter.

FIG. 11 illustrates an IMD placed subcutaneously or submuscularly in apatient's chest with lead(s) positioned to provide a CRM therapy to aheart, and with lead(s) positioned to stimulate a vagus nerve, by way ofexample and not by way of limitation, according to various embodiments.

FIG. 12 illustrates an IMD with lead(s) positioned to provide a CRMtherapy to a heart, and with satellite transducers positioned tostimulate at least one parasympathetic neural target as part of amyocardium conditioning therapy, according to various embodiments.

FIG. 13 is a block diagram illustrating an embodiment of an externalsystem.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

Various embodiments provide myocardial and neural stimulation to effectprophylactic and/or therapeutic cardioprotection. The neural stimulationelicits a parasympathetic response and can include stimulation ofparasympathetic nerve traffic (e.g. vagal stimulation) and/or inhibitionof sympathetic nerve activity. An ischemia detection system can be usedto trigger cardioprotective therapy after ischemia has been detected.

Akt-Mediated Pathway

Various animal models have demonstrated that periodic pacing prior to anischemic insult results in cardioprotective effects such as decreasedinfarct size as well as decreased incidences of arrhythmias. Thedelivery of intermittent ventricular pacing has been proposed to elicitthese cardioprotective effects. One potential cellular mechanism ofaction of cardioprotection is modulation of the Akt-mediated pathway.This Akt-mediated pathway has been implicated in both prophylacticpreconditioning (Hausenloy et al., Ischemic Preconditioning Protects ByActivating Prosurvival Kinases At Reperfusion, Am J Physiol Heart CircPhysiol, 288: H971-76 (2005)) and therapeutic postconditioning (Tsang etal., Postconditioning: A Form Of “Modified Reperfusion” Protects TheMyocardium By Activating The Phosphatidylinositol 3-Kinase-Akt Pathway,Circ Res, 95:230-32 (2004)) in various animal models.

FIG. 1 illustrates therapies to affect a PI3-Akt prosurvival kinase,according to various embodiments of the present subject matter. A kinaseis an enzyme that catalyzes the conversion of a proenzyme to an activeenzyme. A result of affecting the PI3-Akt prosurvival kinase is toreduce apoptosis (programmed cell death). As illustrated in the figure,cardiac protective pacing activates the PI3-Akt prosurvival kinase viaG_(i)-coupled receptors (Krieg et al., Acetylcholine And BradykininTrigger Preconditioning In The Heart Through A Pathway That Includes Aktand NOS, Am J Physiol Heart Circ Physiol, 287:H2606-11 (2005)). As alsoillustrated in FIG. 1, the present subject matter also accesses theAkt-mediated pathway using parasympathetic neural stimulation via Ach(acetylcholine), one of the predominant transmitters in the autonomicnervous system. Ach is a parasympathetic neurotransmitter liberated frompreganglionic and postganglionic endings of parasympathetic fibers,whereupon it acts as a transmitter on the effector organ. Ach causescardiac inhibition, vasodilation, gastrointestinal peristalsis, andother parasympathetic effects. Thus, the Akt-mediated pathway is alsoaffected by vagal nerve stimulation (VNS), or more generally stimulationof a parasympathetic neural target that innervates the myocardium.

The present subject matter protects the heart from injuries associatedwith ischemic events, including MI. This document describes a devicewhich combines periodic myocardium pacing and parasympatheticstimulation to deliver cardioprotective therapy. One device embodiment,for example, delivers pacing therapy at regular (e.g. 5 minutes ofpacing every hour) or random intervals and delivers parasympatheticstimulation. The two therapies may be delivered simultaneously,sequentially, or on different time schedules. The neural stimulation isdelivered to a parasympathetic neural target that innervates themyocardium, such as a vagus nerve, a branch of a vagus nerve, or acardiac fat pad. Various embodiments selectively stimulate a desiredneural pathway within the vagus nerve to produce Ach from the endings ofparasympathetic fibers at desired portions the myocardium.Parasympathetic stimulation is applied at a frequency, amplitude, andperiodicity (e.g. 300 ms pulses at 1-2 mA for 10 seconds every minute)selected to stimulate the parasympathetic neural target. In variousembodiments, the therapies are delivered through different leads, andvarious embodiments deliver the therapies using either the same orindependent pulse generators.

The combination of pacing and parasympathetic stimulation may provide anadditive effect as illustrated with other preconditioning triggers(Morris et al, Angiotensin-Converting Enzyme Inhibitors PotentiatePreconditioning Through Bradykinin B2 Receptor Activation In HumanHeart, J Am Coll Cardiol., 29: 1599-1606 (1997)). The device may becoupled with an ischemia detection system to control the delivery oftherapy after the detection of an ischemic event.

Since the Akt-mediated pathway is also implicated in protection fromischemia/reperfusion, both myocardial and vagal stimulation may provideprotection after the ischemic event. The device may also be used at thetime of scheduled revascularization procedures to protect the myocardiumfrom ischemia/reperfusion injury as well as to provide preconditioningfor possible ischemic events as a result of the revascularizationtherapy. The present subject matter may benefit any patient at high-riskof a first or recurrent myocardial infarction, and may be included in adevice designed to apply therapy for angina, and the pre/postconditioning therapy may be controlled based upon sensing of cardiacischemia.

Myocardial Conditioning

The myocardium conditioning therapy with myocardial pacing andparasympathetic stimulation can be provided according to a variety ofprotocols. Examples of some of these protocols are illustrated here.

FIGS. 2A-2B illustrate myocardium preconditioning and myocardiumpostconditioning, respectively, according to various embodiments of thepresent subject matter. FIG. 2A illustrates a time line with ananticipated or known ischemic event. Preconditioning of the myocardiumoccurs as a prophylactic therapy in preparation for the known oranticipated ischemic event. According to the present subject matter, thepreconditioning includes myocardial pacing and parasympatheticstimulation. For example, the myocardium can be preconditioned inanticipation for surgery, or can be preconditioned based on observed ordetected events that indicate an increased probability of an upcomingischemic event. Examples of such events include a previous myocardialinfarction and angina. FIG. 2B illustrates a time line with a known ordetected ischemic event. Postconditioning of the myocardium occurs as atherapeutic therapy to reduce the size of any infarct area caused by theischemic event. According to the present subject matter, thepostconditioning includes myocardial pacing and parasympatheticstimulation. For example, the postconditioning therapy can be triggeredbased on commands received from a patient or physician after observing amyocardial infarction, or a physician can deliver postconditioningtherapy after a surgical procedure for which the heart was stopped. Inan embodiment, the device detects an ischemic event, and automaticallydelivers the postconditioning therapy. The postconditioning therapy canoccur during the time of reperfusion, for a time after reperfusion, orduring and for a time after reperfusion.

FIGS. 3A-3B illustrate simultaneous and sequential, respectively,delivery of parasympathetic stimulation therapy and pacing therapy,according to various embodiments of the present subject matter. FIG. 3Aillustrates a time line, upon which myocardial pacing 301 to conditionthe myocardium occurs at the same time or independently of theparasympathetic stimulation 302 for conditioning the myocardium. Thefigure illustrates both therapies starting and ending at the same time.Other start and end times are within the scope of the present subjectmatter. FIG. 3B illustrates a time line, upon which the parasympatheticstimulation 302 and myocardial pacing 301 occurs at a staggered orsequential times, such that the parasympathetic stimulation does notoccur at the same time as the myocardial pacing. The figure illustratesparasympathetic stimulation, and then myocardial pacing, and thenparasympathetic stimulation, and then pacing stimulation. Other ordersare within the scope of the present subject matter.

FIGS. 4A-4C illustrate methods for providing pacing and parasympatheticstimulation therapies to condition myocardium, according to variousembodiments of the present subject matter. As illustrated in FIG. 4A, itis determined at 402 whether to implement a therapy to conditionmyocardium. Once it is determined to condition myocardium, the processproceeds to provide a cardiac protection therapy at 403. The therapy 403includes cardiac protection pacing therapy, illustrated at 404, andcardiac protection parasympathetic stimulation therapy, illustrated at405. The therapies 404 and 405 can be performed independently, or can becontrolled to provide an integrated therapy. The therapies 404 and 405also can be timed to avoid simultaneous therapy applications, or can betimed to allow simultaneous therapy applications.

FIG. 4B illustrates a method for providing pacing and parasympatheticstimulation therapies to provide prophylactic preconditioning therapy ofthe myocardium. Reasons for initiating a prophylactic preconditioningtherapy include preparation for a surgical procedure, or an expectedischemic event due to sensed or known risk factors. As illustrated inFIG. 4B, both the cardiac protection pacing therapy and the cardiacprotection parasympathetic stimulation therapy are chronically appliedbecause of sensed or known risk factors, according to variousembodiments.

FIG. 4C illustrates a method for providing pacing and parasympatheticstimulation therapies to provide therapeutic postconditioning therapy ofthe myocardium. Reasons for initiating a therapeutic therapy includepart of a surgical process for reperfusing the myocardium, a sensed orobserved myocardial infarction, or any other sensed ischemic event. Asillustrated in FIG. 4C, both the cardiac protection pacing and thecardiac protection parasympathetic stimulation are applied during atleast a portion of reperfusion and for a period of time after thereperfusion of the myocardium, according to various embodiments. Variousembodiments adjust the timing of the postconditioning therapy to occuronly after reperfusion or to occur only during reperfusion.

Device Examples

FIG. 5 illustrates a device embodiment for providing pacing andparasympathetic stimulation therapies to condition myocardium, accordingto various embodiments of the present subject matter. The illustrateddevice 505 includes a sensing circuit 506, an ischemia detector 507, apulse output circuit 508, a neural stimulator 509, and a control circuit510. Sensing circuit 506 senses one or more signals using a number ofelectrodes and/or one or more sensors. The one or more signals areindicative of ischemic events. Ischemia detector 507 detects theischemic events from the signals. Pulse output circuit 508 deliversmyocardial pacing pulses to the heart, and neural stimulator 509provides neural stimulation to a parasympathetic neural network thatinnervates the heart, such as a vagus nerve, a branch of the vagusnerve, or a cardiac fat pad. Control circuit 510 controls the deliveryof the pacing pulses and neural stimulation based on the one or moresensed signals and/or in response to the detection of each ischemicevent. In various embodiments, the device 505 is substantially containedin an implantable housing of implantable medical device.

The control circuit 510 includes a myocardial stimulation module 511 anda neural stimulation module 512. The myocardial stimulation module 511includes a cardiac protection pacing sequence initiator 513 and acardiac protection pacing timer 514. Cardiac protection pacing sequenceinitiator 513 initiates one or more cardiac protection pacing sequencesin response to the detection of each ischemic event. The one or morecardiac protection pacing sequences each include alternating pacing andnon-pacing periods. The pacing periods each have a pacing durationduring which a plurality of pacing pulse is delivered. The non-pacingperiods each have a non-pacing duration during which no pacing pulse isdelivered. Once a cardiac protection pacing sequence is initiated,cardiac protection pacing timer 514 times that sequence. For example,various embodiments provide pacing for 5 minutes of every hour. Variousevents can also be sensed and used as an input to time the stimulationat desired times. Examples of sensors to detect such events includeactivity sensors. The neural stimulation module 512 includes a cardiacprotection neural stimulation sequence initiator 515 and a cardiacprotection neural stimulation timer 516. Cardiac protection neuralstimulation sequence initiator 515 initiates one or more cardiacprotection neural stimulation sequences in response to the detection ofeach ischemic event. The one or more cardiac protection neuralstimulation sequences each include alternating stimulation andnon-stimulation periods. The stimulation periods each have a durationduring which neural stimulation is delivered to a parasympathetictarget. The non-stimulation periods each have a non-stimulation durationduring which no neural stimulation is delivered. Once a cardiacprotection neural stimulation sequence is initiated, cardiac protectionneural stimulation timer 516 times that sequence. For example, variousembodiments provide neural stimulation (e.g. 300 ms pulses at 1-2 mA)for 10 seconds every minute. According to various embodiments, theneural stimulator circuitry 509 includes modules to set or adjust anyone or any combination of two or more of the following pulse features:the amplitude of the stimulation pulse, the frequency of the stimulationpulse, the burst frequency of the pulse, the wave morphology of thepulse, and the pulse width. The illustrated burst frequency pulsefeature includes burst duration and duty cycle, which can be adjusted aspart of a burst frequency pulse feature or can be adjusted separatelywithout reference to a steady burst frequency.

The neural stimulator may use electrodes to delivery electricalstimulation to a neural target. These neural electrodes can be on thesame lead or on different leads as the cardiac pacing electrodes,depending on the locations of the desired parasympathetic neural target.Some embodiments use other techniques to deliver other energy tostimulate the neural target. For example, some embodiment usetransducers to produce ultrasound or light energy waves to stimulate theneural target.

FIG. 6 illustrates a device embodiment for providing pacing andparasympathetic stimulation to condition myocardium as part ofpreconditioning and postconditioning therapies, according to variousembodiments of the present subject matter. The illustrated device 605includes sensing circuit 606, ischemia detector 607, pulse outputcircuit 608, neural stimulator 609, and a control circuit 610. Sensingcircuit 606 senses the one or more signals indicative of the ischemicevents. Ischemia detector 607 detects the ischemic events from the oneor more signals. Pulse output circuit 608 delivers the pacing pulses toheart. Control circuit 610 controls the delivery of the pacing pulsesand neural stimulation based on the one or more sensed signals and/or inresponse to the detection of each ischemic event. In variousembodiments, the device 605 is substantially contained in an implantablehousing of implantable medical device.

Ischemia detector 607 includes an ischemia analyzer running an automaticischemia detection algorithm to detect the ischemic event from the oneor more signals. In one embodiment, ischemia detector 607 produces anischemia alert signal indicative of the detection of each ischemicevent. The ischemia signal is transmitted to an external system forproducing an alarm signal and/or a warning message for the patientand/or a physician or other caregiver.

In one embodiment, ischemia detector 607 detects the ischemic eventsfrom one or more cardiac signals. Sensing circuit 606 includes a cardiacsensing circuit.

In a specific example, cardiac signals are sensed using a wearable vestincluding embedded electrodes configured to sense surface biopotentialsignals indicative of cardiac activities. The sensed surfacebiopotential signals are transmitted to implantable medical device viatelemetry. In another specific embodiment, ischemia detector 607 detectsthe ischemic events from one or more wireless electrocardiogram (ECG)signals. Sensing circuit 606 includes a wireless ECG sensing circuit. Awireless ECG is a signal approximating the surface ECG and is acquiredwithout using surface (skin contact) electrodes. An example of a circuitfor sensing the wireless ECG is discussed in U.S. Pat. No. 7,299,086,entitled “WIRELESS ECG IN IMPLANTABLE DEVICES,” filed on Mar. 5, 2004,assigned to Cardiac Pacemakers, Inc., which is incorporated by referencein its entirety. An example of a wireless ECG-based ischemia detector isdiscussed in U.S. patent application Ser. No. 11/079,744, entitled“CARDIAC ACTIVATION SEQUENCE MONITORING FOR ISCHEMIA DETECTION,” filedon Mar. 14, 2005, assigned to Cardiac Pacemakers, Inc., which isincorporated by reference in its entirety. In another embodiment,ischemia detector 607 detects the ischemic events from one or moreelectrogram signals. Sensing circuit 606 includes an electrogram sensingcircuit. Examples of an electrogram-based ischemia detector arediscussed in U.S. Pat. No. 6,108,577, entitled, “METHOD AND APPARATUSFOR DETECTING CHANGES IN ELECTROCARDIOGRAM SIGNALS,” and U.S. Pat. No.7,340,303, entitled “EVOKED RESPONSE SENSING FOR ISCHEMIA DETECTION,”filed on Sep. 25, 2001, both assigned to Cardiac Pacemakers, Inc., whichare incorporated herein by reference in their entirety.

In another embodiment, ischemia detector 607 detects the ischemic eventsfrom one or more impedance signals. Sensing circuit 606 includes animpedance sensing circuit to sense one or more impedance signals eachindicative of a cardiac impedance or a transthoracic impedance. Ischemiadetector 607 includes an electrical impedance based sensor using a lowcarrier frequency to detect the ischemic events from an electricalimpedance signal. Tissue electrical impedance has been shown to increasesignificantly during ischemia and decrease significantly after ischemia,as discussed in Dzwonczyk, et al. IEEE Trans. Biomed. Eng., 51 (12):2206-09 (2004). The ischemia detector senses low frequency electricalimpedance signal between electrodes interposed in the heart, and detectsthe ischemia as abrupt changes in impedance (such as abrupt increases invalue).

In another embodiment, ischemia detector 607 detects the ischemic eventsfrom one or more signals indicative of heart sounds. Sensing circuit 606includes a heart sound sensing circuit. The heart sound sensing circuitsenses the one or more signals indicative of heart sounds using one ormore sensors such as accelerometers and/or microphones. Such sensors areincluded in implantable medical device or incorporated into lead system.Ischemia detector 607 detects the ischemic event by detectingpredetermined type heart sounds, predetermined type heart soundcomponents, predetermined type morphological characteristics of heartsounds, or other characteristics of heart sounds indicative of ischemia.

In another embodiment, ischemia detector 607 detects the ischemic eventsfrom one or more pressure signals. Sensing circuit 606 includes apressure sensing circuit coupled to one or more pressure sensors. In aspecific embodiment, the pressure sensor is an implantable pressuresensor sensing a signal indicative of an intracardiac or intravascularpressure whose characteristics are indicative of ischemia.

In another embodiment, ischemia detector 607 detects the ischemic eventfrom one or more acceleration signals each indicative of regionalcardiac wall motion. Sensing circuit 606 includes a cardiac motionsensing circuit coupled to one or more accelerometers each incorporatedinto a portion of a lead positioned on or in the heart. The ischemiadetector detects ischemia as an abrupt decrease in the amplitude oflocal cardiac accelerations.

In another embodiment, ischemia detector 607 detects the ischemic eventfrom a heart rate variability (HRV) signal indicative of HRV. Sensingcircuit 606 includes an HRV sensing circuit to sense the HRV and producethe HRV signal, which is representative of an HRV parameter. HRV is thebeat-to-beat variance in cardiac cycle length over a period of time. TheHRV parameter includes any parameter being a measure of the HRV,including any qualitative expression of the beat-to-beat variance incardiac cycle length over a period of time. In a specific embodiment,the HRV parameter includes the ratio of Low-Frequency (LF) HRV toHigh-Frequency (HF) HRV (LF/HF ratio). The LF HRV includes components ofthe HRV having frequencies between about 0.04 Hz and 0.15 Hz. The HF HRVincludes components of the HRV having frequencies between about 0.15 Hzand 0.40 Hz. The ischemia detector detects ischemia when the LF/HF ratioexceeds a predetermined threshold. An example of an LF/HF ratio-basedischemia detector is discussed in U.S. Pat. No. 7,215,992, entitled“METHOD FOR ISCHEMIA DETECTION BY IMPLANTABLE CARDIAC DEVICE,” filed onSep. 23, 2003, assigned to Cardiac Pacemakers, Inc., which isincorporated by reference in its entirety.

Control circuit 610 includes a pacing mode switch 617, a pacing modecontroller 618, a cardiac protection sequence initiator 619, and acardiac protection timer 620. Control circuit 610 allows the device tocontrol the delivery of the cardiac protection therapy (pacing andneural stimulation) as well as other pacing therapies. This allows thefunction of cardiac protection pacing to be included in an implantablemedical device that delivers pacing therapies on a long-term basis, suchas for treatment of bradycardia and heart failure. In variousembodiments, cardiac protection pacing therapy includes a temporarypacing therapy delivered for one or more brief periods in response tothe detection of each ischemia event, and the implantable medical devicealso delivers a chronic pacing therapy such as a bradycardia pacingtherapy, or CRT. In other embodiments, the cardiac protection pacingtherapy is the only pacing therapy delivered, or the cardiac protectionpacing therapy is the only pacing therapy programmed to be delivered forat least a certain period of time.

Each pacing therapy is delivered by delivering pacing pulses inaccordance with a predetermined pacing mode. Pacing mode switch 617switches the pacing mode from a chronic pacing mode to a temporarypacing mode when a cardiac protection pacing sequence is initiated andto switch the pacing mode from the temporary pacing mode to the chronicpacing mode when the cardiac protection pacing sequence is completed.Pacing mode controller 618 controls the delivery of the pacing pulsesfrom pulse output circuit 608 according to the pacing mode as selectedby pacing mode switch 617. The temporary pacing mode refers to thepacing mode used in a cardiac protection pacing therapy, which is atemporary pacing therapy. The chronic pacing mode refers to the pacingmode used in a chronic pacing therapy such as a bradycardia pacingtherapy, or CRT. In one embodiment, the temporary pacing mode issubstantially different from the chronic pacing mode, such that thecardiac protection pacing therapy changes the distribution of stress inthe myocardium, thereby triggering the intrinsic myocardial protectivemechanism against ischemic damage to the myocardial tissue.

Cardiac protection sequence initiator 619 initiates one or more cardiacprotection pacing sequences and neural stimulation sequences in responseto the detection of each ischemic event. In one embodiment, cardiacprotection sequence initiator 619 also initiates one or more cardiacprotection sequences in response to one or more commands issued by theuser through external system. For example, following a diagnosis ofvulnerable plaque indicative of a high risk for MI, a physician appliesa preconditioning therapy by starting a cardiac protection sequence byissuing such a command. Cardiac protection timer 620 times the one ormore cardiac protection sequences including the alternating stimulatingand non-stimulating periods.

In one embodiment, the one or more cardiac protection sequencesinitiated in response to the detection of each ischemic event include atleast one postconditioning sequence and at least one prophylacticpreconditioning sequences. Postconditioning sequence initiator 621initiates the postconditioning sequence in response to the detection ofan ischemic event. In one embodiment, postconditioning sequenceinitiator 621 initiates the postconditioning sequence when the end ofthe ischemic event is detected. In one embodiment, the end of theischemic event is detected when the ischemic event is no longer detectedby ischemia detector. In one embodiment, postconditioning sequenceinitiator 621 initiates the postconditioning pacing sequence when apost-ischemia time interval expires. The post-ischemia time intervalstarts when the end of the ischemic event is detected and is up toapproximately 10 minutes, with approximately 30 seconds being a specificexample. In one embodiment, the post-ischemia time interval is chosensuch that the postconditioning sequence is initiated after thereperfusion phase following the ischemic event has started. In anotherembodiment, postconditioning sequence initiator 621 initiates thepostconditioning sequence in response to one or more postconditioningcommands issued by the user.

In one embodiment, preconditioning sequence initiator 622 initiates theprophylactic preconditioning sequences after the end of the ischemicevent is detected and the postconditioning sequence is completed. In oneembodiment, preconditioning sequence initiator 622 initiates theprophylactic preconditioning pacing sequences on a periodic basis usinga predetermined period such as, according to various embodiments,periods in a range of approximately 24 hours to 72 hours. In anotherembodiment, preconditioning sequence initiator 622 initiates theprophylactic preconditioning pacing sequences according to a programmedpreconditioning schedule. In another embodiment, preconditioningsequence initiator 622 initiates the prophylactic preconditioning pacingsequences in response to one or more preconditioning commands issued bythe user. Various embodiments use sensor input (e.g. activity orrespiration sensor) to determine a desired time to initiate thesequence.

Postconditioning timer 623 times the postconditioning sequence includingalternating postconditioning stimulation and non-stimulation periods.The postconditioning pacing periods each have a postconditioning pacingduration during which a plurality of pacing pulses is delivered. Thepostconditioning non-pacing periods each have a postconditioningnon-pacing duration during which no pacing pulse is delivered.Preconditioning timer 624 times the prophylactic preconditioningsequences including alternating preconditioning stimulation andnon-stimulation periods. The preconditioning periods each have apreconditioning stimulation duration during which pacing pulses andneural stimulation is delivered. The pacing and neural stimulation canbe delivered simultaneously or sequentially.

In one embodiment, control circuit 610 detects an arrhythmia andsuspends the one or more cardiac protection pacing sequences in responseto the detection of the arrhythmia. Control circuit includes anarrhythmia detector to detect one or more predetermined types ofarrhythmia. In one embodiment, cardiac protection sequence initiatorcancels, holds, or otherwise adjusts the timing of the initiation of acardiac protection sequence in response to a detection of arrhythmia. Inone embodiment, cardiac protection timer terminates or suspends acardiac protection pacing sequence in response to the detection of anarrhythmia that occurs during the cardiac protection sequence. In aspecific embodiment, postconditioning sequence initiator cancels theinitiation of a postconditioning sequence in response to the detectionof arrhythmia. In a specific embodiment, preconditioning sequenceinitiator holds the initiation of a prophylactic preconditioningsequence in response to the detection of arrhythmia unit the arrhythmiais no longer detected. In one embodiment, cardiac protection timerterminates or suspends a cardiac protection sequence in response to thedetection of an arrhythmia that occurs during the cardiac protectionsequence.

FIG. 7 illustrates an implantable medical device (IMD) 725 having aneural stimulation (NS) component 726 and cardiac rhythm management(CRM) component 727, according to various embodiments of the presentsubject matter.

The illustrated device includes a controller 728 and memory 729.According to various embodiments, the controller includes hardware,software, or a combination of hardware and software to perform theneural stimulation and CRM functions. For example, the programmedtherapy applications discussed in this disclosure are capable of beingstored as computer-readable instructions embodied in memory and executedby a processor. According to various embodiments, the controllerincludes a processor to execute instructions embedded in memory toperform the neural stimulation and CRM functions. Examples of CRMfunctions include bradycardia pacing, antitachycardia therapies such asantitachycardia pacing and defibrillation, and CRT. The controller alsoexecutes instructions to detect ischemia. The illustrated device furtherincludes a transceiver 730 and associated circuitry for use tocommunicate with a programmer or another external or internal device.Various embodiments include a telemetry coil.

The CRM therapy section 727 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The CRM therapy section includes a pulsegenerator 728 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry 729to detect and process sensed cardiac signals. An interface 730 isgenerally illustrated for use to communicate between the controller 728and the pulse generator 728 and sense circuitry 729. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 726 includes components, under the control of thecontroller, to stimulate a neural stimulation target and/or senseparameters associated with nerve activity or surrogates of nerveactivity such as blood pressure and respiration. Three interfaces 731are illustrated for use to provide neural stimulation. However, thepresent subject matter is not limited to a particular number interfaces,or to any particular stimulating or sensing functions. Pulse generators732 are used to provide electrical pulses to transducer or transducersfor use to stimulate a neural stimulation target. According to variousembodiments, the pulse generator includes circuitry to set, and in someembodiments change, the amplitude of the stimulation pulse, thefrequency of the stimulation pulse, the burst frequency of the pulse,and the morphology of the pulse such as a square wave, triangle wave,sinusoidal wave, and waves with desired harmonic components to mimicwhite noise or other signals. Sense circuits 733 are used to detect andprocess signals from a sensor, such as a sensor of nerve activity, bloodpressure, respiration, and the like. The interfaces 731 are generallyillustrated for use to communicate between the controller 728 and thepulse generator 732 and sense circuitry 733. Each interface, forexample, may be used to control a separate lead. Various embodiments ofthe NS therapy section only include a pulse generator to stimulateneural targets such a vagus nerve.

FIG. 8 shows a system diagram of an embodiment of a microprocessor-basedimplantable device. The device 833 is equipped with multiple sensing andpacing channels which may be physically configured to sense and/or pacemultiple sites in the atria or the ventricles, and to provide neuralstimulation. The illustrated device can be configured for myocardialstimulation (e.g. myocardium conditioning pacing, bradycardia pacing,defibrillation, CRT) and neural stimulation (e.g. myocardiumconditioning parasympathetic stimulation). The multiple sensing/pacingchannels may be configured, for example, with one atrial and twoventricular sensing/pacing channels for delivering biventricularresynchronization therapy, with the atrial sensing/pacing channel usedto deliver the biventricular resynchronization therapy in an atrialtracking mode as well as to pace the atria if required. The controller834 of the device is a microprocessor which communicates with memory 835via a bidirectional data bus. The controller could be implemented byother types of logic circuitry (e.g., discrete components orprogrammable logic arrays) using a state machine type of design. As usedherein, the term “circuitry” should be taken to refer to either discretelogic circuitry or to the programming of a microprocessor.

Shown in FIG. 8, by way of example, are three sensing and pacingchannels, such as can be used to provide myocardial stimulation/pacing,designated “A” through “C” comprising bipolar leads with ring, orproximal, electrodes 836A-C and distal, or tip, electrodes 837A-C, pulsegenerators 838A-C, sensing amplifiers 839A-C, and channel interfaces840A-C. Each channel thus includes a pacing channel made up of the pulsegenerator connected to the electrode and a sensing channel made up ofthe sense amplifier connected to the electrode. The channel interfaces840A-C communicate bidirectionally with the microprocessor 834, and eachinterface may include analog-to-digital converters for digitizingsensing signal inputs from the sensing amplifiers and registers that canbe written to by the microprocessor in order to output pacing pulses,change the pacing pulse amplitude, and adjust the gain and thresholdvalues for the sensing amplifiers. The sensing circuitry of thepacemaker detects a chamber sense, either an atrial sense or ventricularsense, when an electrogram signal (i.e., a voltage sensed by anelectrode representing cardiac electrical activity) generated by aparticular channel exceeds a specified detection threshold. Pacingalgorithms used in particular pacing modes employ such senses to triggeror inhibit pacing, and the intrinsic atrial and/or ventricular rates canbe detected by measuring the time intervals between atrial andventricular senses, respectively. The pacing algorithms also include theappropriate preconditioning and postconditioning pacing algorithms.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 841 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring, or proximal, and tip, or distal,electrodes of a lead or in a unipolar mode using only one of theelectrodes of the lead with the device housing or can 842 serving as aground electrode.

Also shown in FIG. 8, by way of example, are nerve stimulation channelsdesignated “D” and “E.” Neural stimulation channels are incorporatedinto the device. These channels can be used to deliver neuralstimulation to elicit a parasympathetic response as part of acardioprotective therapy. The illustrated channels include leads withelectrodes 843D and 844D and electrodes 843E and 844E, a pulse generator845D and 845E, and a channel interface 846D and 846E. The illustratedbipolar arrangement is intended as a non-exclusive example. Other neuralstimulation electrode arrangements are within the scope of the presentsubject matter. Other embodiments may use unipolar leads in which casethe neural stimulation pulses are referenced to the can or anotherelectrode. The pulse generator for each channel outputs a train ofneural stimulation pulses which may be varied by the controller as toamplitude, frequency, duty-cycle, pulse duration, and wave morphology,for example. A shock pulse generator 847 is also interfaced to thecontroller for delivering a defibrillation shock via a pair of shockelectrodes 848A and 848B to the atria or ventricles upon detection of ashockable tachyarrhythmia.

The illustrated controller includes a module for controlling neuralstimulation (NS) therapy and module for controlling myocardial therapy.As illustrated, the NS therapy module includes a module for performingmyocardial conditioning (e.g. vagal nerve stimulation or stimulation ofa cardiac fat pad). Also as illustrated, the myocardial therapy moduleincludes a module for controlling myocardial conditioning pacing, amodule for controlling bradycardia pacing therapies, a module forcontrolling defibrillation therapies, and a module for controlling CRT.The illustrated controller also includes a module to detect ischemia,used to trigger myocardial conditioning, including both parasympatheticstimulation and myocardial pacing.

The controller controls the overall operation of the device inaccordance with programmed instructions stored in memory, includingcontrolling the delivery of paces via the pacing channels, interpretingsense signals received from the sensing channels, and implementingtimers for defining escape intervals and sensory refractory periods. Thecontroller is capable of operating the device in a number of programmedpacing modes which define how pulses are output in response to sensedevents and expiration of time intervals. Most pacemakers for treatingbradycardia are programmed to operate synchronously in a so-calleddemand mode where sensed cardiac events occurring within a definedinterval either trigger or inhibit a pacing pulse. Inhibited demandpacing modes utilize escape intervals to control pacing in accordancewith sensed intrinsic activity such that a pacing pulse is delivered toa heart chamber during a cardiac cycle only after expiration of adefined escape interval during which no intrinsic beat by the chamber isdetected. Escape intervals for ventricular pacing can be restarted byventricular or atrial events, the latter allowing the pacing to trackintrinsic atrial beats. CRT is most conveniently delivered inconjunction with a bradycardia pacing mode where, for example, multipleexcitatory stimulation pulses are delivered to multiple sites during acardiac cycle in order to both pace the heart in accordance with abradycardia mode and provide pre-excitation of selected sites. Anexertion level sensor 849 (e.g., an accelerometer, a minute ventilationsensor, or other sensor that measures a parameter related to metabolicdemand) enables the controller to adapt the pacing rate in accordancewith changes in the patient's physical activity and can enable thecontroller to modulate the delivery of neural stimulation and/or cardiacpacing. A telemetry interface 850 is also provided which enables thecontroller to communicate with an external programmer or remote monitor.

System Examples

FIG. 9 illustrates a system 951 including an implantable medical device

(IMD) 952 and an external system or device 953, according to variousembodiments of the present subject matter. Various embodiments of theIMD 952 include a combination of NS and CRM functions. The IMD may alsodeliver biological agents and pharmaceutical agents. The external system953 and the IMD 952 are capable of wirelessly communicating data andinstructions. In various embodiments, for example, the external systems953 and IMD 952 use telemetry coils to wirelessly communicate data andinstructions. Thus, the programmer can be used to adjust the programmedtherapy provided by the IMD 952, and the IMD can report device data(such as battery and lead resistance) and therapy data (such as senseand stimulation data) to the programmer using radio telemetry, forexample. According to various embodiments, the IMD 952 stimulates aparasympathetic target to provide a myocardium conditioning therapy, andpaces myocardium as part of the myocardium conditioning therapy.

In one embodiment, in addition to the cardiac protection pacing therapy,the IMD 952 also delivers one or more other cardiac pacing therapies,such a bradycardia pacing therapy, and CRT. If another pacing therapy isbeing delivered when a cardiac protection pacing sequence is to beinitiated, that pacing therapy is temporarily suspended to allow thedelivery of the cardiac protection pacing therapy and resumed uponcompletion of the cardiac protection pacing sequence.

External system 953 allows a user such as a physician or other caregiveror a patient to control the operation of IMD 952 and obtain informationacquired by the

IMD 952. In one embodiment, external system 953 includes a programmercommunicating with the IMD 952 bi-directionally via a telemetry link. Inanother embodiment, the external system 953 is a patient managementsystem including an external device communicating with a remote devicethrough a telecommunication network. The external device is within thevicinity of the IMD 952 and communicates with IMD bi-directionally via atelemetry link. The remote device allows the user to monitor and treat apatient from a distant location. The patient monitoring system isfurther discussed below.

The telemetry link provides for data transmission from implantablemedical device to external system. This includes, for example,transmitting real-time physiological data acquired by IMD, extractingphysiological data acquired by and stored in IMD, extracting therapyhistory data stored in implantable medical device, and extracting dataindicating an operational status of IMD (e.g., battery status and leadimpedance). Telemetry link also provides for data transmission fromexternal system to IMD. This includes, for example, programming IMD toacquire physiological data, programming IMD to perform at least oneself-diagnostic test (such as for a device operational status), andprogramming IMD to deliver at least one therapy.

FIG. 10 illustrates a system 1054 including an external device 1055, animplantable neural stimulator (NS) device 1056 and an implantablecardiac rhythm management (CRM) device 1057, according to variousembodiments of the present subject matter. Various aspects involve amethod for communicating between an NS device 1056 and a CRM device 1057or other cardiac stimulator. The NS device 1056 delivers parasympatheticstimulation for a myocardium conditioning therapy, and the CRM device1057 delivers myocardium pacing therapy for the myocardium conditioningtherapy. In various embodiments, this communication allows one of thedevices 1056 or 1057 to deliver more appropriate therapy (i.e. moreappropriate NS therapy or CRM therapy) based on data received from theother device. Some embodiments provide on-demand communications. Invarious embodiments, this communication allows each of the devices todeliver more appropriate therapy (i.e. more appropriate NS therapy andCRM therapy) based on data received from the other device. Theillustrated NS device and the CRM device are capable of wirelesslycommunicating with each other, and the external system is capable ofwirelessly communicating with at least one of the NS and the CRMdevices. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.Rather than providing wireless communication between the NS and CRMdevices, various embodiments provide a communication cable or wire, suchas an intravenously-fed lead, for use to communicate between the NSdevice and the CRM device.

FIG. 11 illustrates an IMD 1158 placed subcutaneously or submuscularlyin a patient's chest with lead(s) 1159 positioned to provide a CRMtherapy to a heart 1160, and with lead(s) 1161 positioned to stimulate avagus nerve, by way of example and not by way of limitation. The leads1159 can be used to delivery the myocardium pacing to conditionmyocardium. According to various embodiments, the leads 1159 arepositioned in or proximate to the heart to provide a desired cardiacpacing therapy. In some embodiments, the lead(s) 1159 are positioned inor proximate to the heart to provide a desired defibrillation therapy.In some embodiments, the lead(s) 1159 are positioned in or proximate tothe heart to provide a desired CRT therapy. Some embodiments place theleads in positions with respect to the heart that enable the lead(s) todeliver the combinations of at least two of the pacing, defibrillationand CRT therapies. According to various embodiments, neural stimulationlead(s) 1161 are subcutaneously tunneled to a neural target, and canhave a nerve cuff electrode to stimulate the neural target. Some leadembodiments are intravascularly fed into a vessel proximate to theneural target, and use transducer(s) within the vessel totransvascularly stimulate the neural target. For example, someembodiments stimulate the vagus using electrode(s) positioned within theinternal jugular vein.

FIG. 12 illustrates an IMD 1262 with lead(s) 1263 positioned to providea CRM therapy to a heart 1264, and with satellite transducers 1265positioned to stimulate at least one parasympathetic neural target aspart of a myocardium conditioning therapy. The satellite transducers areconnected to the IMD, which functions as the planet for the satellites,via a wireless link. Stimulation and communication can be performedthrough the wireless link. Examples of wireless links include RF linksand ultrasound links. Although not illustrated, some embodiments performmyocardial stimulation using wireless links. Examples of satellitetransducers include subcutaneous transducers, nerve cuff transducers andintravascular transducers.

The external system illustrated in FIGS. 9-10 includes a programmer, insome embodiments, and includes a patient management system in otherembodiments. FIG. 13 is a block diagram illustrating an embodiment of anexternal system 1366. As illustrated, external system 1366 is a patientmanagement system including an external device 1367, a telecommunicationnetwork 1368, and a remote device 1369. External device 1366 is placedwithin the vicinity of an IMD and includes external telemetry system1370 to communicate with the IMD. Remote device(s) 1369 is in one ormore remote locations and communicates with external device 1367 throughnetwork 1368, thus allowing a physician or other caregiver to monitorand treat a patient from a distant location and/or allowing access tovarious treatment resources from the one or more remote locations. Inone embodiment, remote device 1369 includes a user interface 1371. Thisallows the user to initiate and/or adjust the cardiac protection pacingtherapy.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the term module is intended to encompass software implementations,hardware implementations, and software and hardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. In variousembodiments, the methods provided above are implemented as a computerdata signal embodied in a carrier wave or propagated signal, thatrepresents a sequence of instructions which, when executed by aprocessor cause the processor to perform the respective method. Invarious embodiments, methods provided above are implemented as a set ofinstructions contained on a computer-accessible medium capable ofdirecting a processor to perform the respective method. In variousembodiments, the medium is a magnetic medium, an electronic medium, oran optical medium.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement which is calculated to achieve the same purpose maybe substituted for the specific embodiment shown. This application isintended to cover adaptations or variations of the present subjectmatter. It is to be understood that the above description is intended tobe illustrative, and not restrictive. Combinations of the aboveembodiments as well as combinations of portions of the above embodimentsin other embodiments will be apparent to those of skill in the art uponreviewing the above description. The scope of the present subject mattershould be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled.

1. A system, comprising: a neural stimulator adapted to generate aneural stimulation signal; a pulse generator adapted to generate apacing signal to provide myocardium pacing; and a controller adapted tocontrol the neural stimulator and the pulse generator to provide acardioprotective conditioning therapy, the conditioning therapyincluding neural stimulation to elicit a parasympathetic response andmyocardium pacing, wherein to provide the myocardium pacing for thecardioprotective conditioning therapy, the controller is configured tocontrol the pulse generator to deliver a programmed myocardial pacingsequence, wherein the controller is configured to initiate and time asequence of myocardial pacing pulses for the programmed myocardialpacing sequence, wherein the sequence of myocardial pacing pulsesincludes alternating pacing periods with a programmed pacing durationand non-pacing periods with a programmed non-pacing duration, whereineach pacing period in the programmed myocardial pacing sequence includesthe timed sequence of myocardial pacing pulses delivered to a myocardiumfor the duration of each of the pacing periods, and wherein myocardialpacing pulses are not delivered during each of the non-pacing periods.2. The system of claim 1, further comprising an ischemia detector todetect an ischemia event, wherein the controller is adapted to providethe conditioning therapy in response to a signal from the ischemiadetector indicative of the ischemia event.
 3. The system of claim 1,wherein the neural stimulator and the pulse generator are integrated ina single pulse generator circuit.
 4. The system of claim 1, wherein theneural stimulator and the pulse generator are distinct.
 5. The system ofclaim 1, wherein the conditioning therapy includes a therapeuticpostconditioning therapy for a detected ischemia event.
 6. The system ofclaim 1, wherein the conditioning therapy includes a prophylacticpreconditioning therapy for an anticipated ischemia event.
 7. The systemof claim 1, further comprising an ischemia detector to detect anischemia event, wherein the controller is adapted to provide atherapeutic postconditioning therapy for a detected ischemia event inresponse to a signal from the ischemia detector indicative of thedetected ischemia event, and then provide a prophylactic preconditioningtherapy for an anticipated ischemia event after the detected ischemiaevent.
 8. The system of claim 1, wherein the controller is adapted tocontrol the neural stimulator and the pulse generator to independentlyprovide the neural stimulation and the myocardium pacing.
 9. The systemof claim 1, wherein the controller is adapted to control the neuralstimulator and the pulse generator to integrate the delivery of theneural stimulation and the delivery of the myocardium pacing.
 10. Thesystem of claim 9, wherein the controller is adapted to control theneural stimulator and the pulse generator to prevent the simultaneousdelivery of the neural stimulation and the myocardium pacing.
 11. Thesystem of claim 9, wherein the controller is adapted to control theneural stimulator and the pulse generator to coordinate the simultaneousdelivery of the neural stimulation and the myocardium pacing.
 12. Thesystem of claim 1, further comprising at least one electrode adapted tostimulate a vagus nerve.
 13. The system of claim 1, further comprisingan intravascularly-fed lead connecting the at least one electrode to theneural stimulator, the lead and the at least one electrode being adaptedfor positioning of the at least one electrode in an internal jugularvein to transvascularly stimulate the vagus nerve.
 14. The system ofclaim 1, further comprising a subcutaneously-fed lead connected to theat least one electrode to the neural stimulator, the at least oneelectrode including a nerve cuff electrode adapted to stimulate thevagus nerve.
 15. The system of claim 1, wherein the controller, theneural stimulator and the pulse generator are incorporated in a singleimplantable medical device.
 16. The system of claim 1, wherein theneural stimulator is incorporated in an implantable neural stimulatorand the pulse generator is incorporated in a cardiac rhythm management(CRM) device.
 17. The system of claim 1, wherein the controller isadapted to control the pulse generator to provide myocardium pacing atregular intervals.
 18. The system of claim 1, wherein the controller isadapted to control the neural stimulator to provide neural stimulationfor approximately ten seconds every minute.
 19. The system of claim 1,wherein the controller is adapted to control the neural stimulator toprovide neural stimulation to stimulate parasympathetic nerve traffic.20. The system of claim 1, wherein the controller is adapted to controlthe neural stimulator to provide neural stimulation to inhibitsympathetic nerve traffic.